β-oxo-β-benzenepropanethioamide compounds

ABSTRACT

The  beta -oxo- beta -benzenepropanethioamide derivative of the present invention has potassium channel opening action and is useful for treatment of hypertension, asthma, hypersensitive colon syndrome, and enteritis through pharmacological actions including blood vessel dilation, bronchial tract dilation, relaxation of gastrointestinal tract smooth muscle, and the like. The present invention also includes a pharmaceutical composition containing, as the active ingredient, the compound of the present invention and a method for producing the same.

FIELD OF THE INVENTION

The present invention relates to novel β-oxo-β-benzenepropanethioamidederivatives. More specifically, the present invention relates to novelβ-oxo-β-benzenepropanethioamide derivatives and the pharmaceuticallyacceptable acid addition salts thereof, having potassium channel openingaction and which are useful for treatment of hypertension, asthma,hypersensitive colon syndrome and enteritis through pharmacologicalactions including blood vessel dilation, bronchial tract dilation,relaxation of gastrointestinal tract smooth muscle, and the like.

BACKGROUND OF THE INVENTION

As β-oxo-β-benzenepropanethioamide derivatives, there have been known N,α,α-trimethyl-β-oxobenzenepropanethioamide (Compound of the followingformula (A)) and N-phenyl-α,α-dimethyl-β-oxobenzenepropanethioamide(Compound of the following formula (B)) (Bull. Soc. Chim., Fr., 1975,829), and as the α-monomethyl derivatives thereof, there have been knownthe N-propyl derivative (Compound of the following formula (C))(Tetrahedron 44, 3159(19)), the N-phenyl derivative (Compounds of thefollowing formulas (D) and (E)) (J. Chem. Soc. Perkin I, 1988, 1739) and4-(2-methyl-3-oxo-3-phenyl-1-thioxopropyl) morpholine (Compound of thefollowing formula (F)) (Synthesis 1988, 556), but none of thepharmaceutical actions thereof has been reported yet. ##STR1## (In theabove formulas, Me represents methyl group; nPr represents n-propylgroup; and Ph represents phenyl group.)

Alternatively, a variety of compounds having anti-hypertensive actionhave been proposed, and it has been known, for example, thatthioformamide derivatives having a heterocyclic ring such as pyridineand quinoline have an ability to lower the arterial pressure inspontaneous hypertensive rats (SHR) (see Japanese Patent Laid-open Nos.130974/1980, 42687/1982, 7188/1984, 232281/1984, 211566/1989,30875/1989, and 273/1990).

SUMMARY OF THE INVENTION

The present inventors have made investigations intensively based onthese findings, and have found that the compounds of the presentinvention have potassium channel opening action. Thus, the inventorshave achieved the present invention.

The gist of the present invention resides inβ-oxo-β-benzenepropanethioamide derivatives represented by the followinggeneral formula (I): ##STR2## (in the above general formula (I), R¹ andR² independently represent hydrogen atom, an alkyl group of C₁ to C₆ ora cycloalkyl group of C₃ to C₆, or R¹ and R², when taken together,represent an alkylene group of C₃ to C₆ ; R³ represents hydrogen atom,an alkyl group of C₁ to C₆ or a cycloalkyl group of C₃ to C₆ ; R⁴represents an alkyl group of C₁ to C₆ or a cycloalkyl group of C₃ to C₆; or R³ and R⁴, when taken together, represent an alkylene group of C₂to C₅ ; X¹, X² and X³ independently represent hydrogen atom, a halogenatom, an alkyl group of C₁ to C₆, a cycloalkyl group of C₃ to C₆, analkoxy group of C₁ to C₆, trifluoromethyl group, cyano group, nitrogroup, a dialkylamino group of C₂ to C₁₂, sulfamoyl group, or afive-membered or six-membered heterocyclic group containing nitrogenatom as the hetero atom, which group may or may not have a substituent,except for the case that R¹ represents hydrogen atom; R² representsn-propyl group; R³ represents hydrogen atom; R⁴ represents methyl group;X¹, X² and X³ represent hydrogen atom; and the case that R¹ representshydrogen atom; R², R³ and R⁴ represent methyl group; and X¹, X² and X³represent hydrogen atom.)

The present invention also provides a pharmaceutical compositioncontaining, as an active ingredient, a β-oxo-β-benzenepropanethioamidederivative of the above formula (I), an optical antipode thereof or asalt thereof.

The present invention also provides a process for the preparation ofβ-oxo-β-benzenepropanethioamide derivatives of the above formula (I),optical antipodes thereof or salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be explained in detail. The compounds ofthe present invention are β-oxo-β-benzenepropanethioamide derivativesrepresented by the following general formula (I): ##STR3## {in the aboveformula (I), R¹ and R² independently represent hydrogen atom, an alkylgroup of C₁ to C₆ (methyl group, propyl group, hexyl group, etc.) or acycloalkyl group of C₃ to C₆ (cyclopropyl group, cyclohexyl group,etc.), or R¹ and R², when taken together, represent an alkylene group ofC₃ to C₆ (representing azetidine ring, hexamethyleneimine ring, etc.together with the nitrogen atom to which they are bonded); R³ representshydrogen atom, an alkyl group of C₁ to C₆ (methyl group, propyl group,hexyl group, etc.) or a cycloalkyl group of C₃ to C₆ (cyclopropyl group,cyclohexyl group, etc.); R⁴ represents an alkyl group of C₁ to C₆(methyl group, propyl group, hexyl group, etc.) or a cycloalkyl group ofC₃ to C₆ (cyclopropyl group, cyclohexyl group, etc.); or R³ and R⁴, whentaken together, represent an alkylene group of C₂ to C₅ (representingcyclopropane ring, cyclohexane ring, etc. together with the carbon atomsthe which they are bonded); X¹, X² and X³ independently representhydrogen atom, a halogen atom (fluorine atom, chlorine atom, bromineatom, iodine atom, etc.), an alkyl group of C₁ to C₆ (methyl group,propyl group, hexyl group, etc.), a cycloalkyl group of C₃ to C₆(cyclopropyl group, cyclohexyl group, etc. ), an alkoxy group of C₁ toC₆ (methoxy group, propoxy group, hexyloxy group), trifluoromethylgroup, cyano group, nitro group, a dialkylamino group of C₂ to C₁₂(dimethylamino group, diethylamino group, diisopropylamino group, etc.),sulfamoyl group, a five-membered or six-membered heterocyclic groupcontaining nitrogen atom as the hetero atom (pyrrolyl group, imidazolylgroup, pyrazolyl group, triazolyl group, thiazolyl group, oxazolylgroup, pyridyl group, pyridazinyl group, pyridazinonyl group,pyrrolidonyl group, pyridonyl group, pyrimidinyl group, etc.), whichgroup may or may not have a substituent [an alkyl group of C₁ to C₆(methyl group, propyl group, hexyl group, etc.), an alkoxy group of C₁to C₆ (methoxy group, propoxy group, hexyloxy group, etc.), a halogenatom (fluorine atom, chlorine atom, bromine atom, iodine atom, etc.),cyano group, phenyl group, an alkylthio group of C₁ to C₆ (methylthiogroup, propylthio group, hexylthio group, etc.), a haloalkyl group of C₁to C₆ (methyl group, propyl group, hexyl group, etc., having one or moresubstituents selected from fluorine atom, chlorine atom, bromine atom,iodine atom, etc.)], except for the case that R¹ represents hydrogenatom; R² represents n-propyl group; R³ represents hydrogen atom; R⁴represents methyl group; X¹, X² and X³ represent hydrogen atom; and thecase that R¹ represents hydrogen atom; R², R³ and R⁴ represent methylgroup; and X¹, X² and X³ represent hydrogen atom.)}, or thepharmaceutically acceptable acid addition salts thereof (salts ofmineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid,etc., or organic acids such as acetic acid, malonic acid, fumaric acid,maleic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.)

Preferred examples of the compounds of the present invention include,among the above compounds, a compound wherein at least one of X¹, X² andX³ represents a halogen atom, an alkyl group of C₁ to C₆, a cycloalkylgroup of C₃ to C₅, an alkoxy group of C₁ to C₆, trifluoromethyl group,cyano group, nitro group, a dialkylamino group of C₂ to C₁₂, sulfamoylgroup, a five-membered or six-membered heterocyclic group containingnitrogen atom as the hetero atom, which group may or may not have asubstituent.

More preferred compounds include, among the above compounds, a compoundwherein at least one of X¹, X² and X³ represents a five-membered orsix-membered heterocyclic group containing nitrogen atom as the heteroatom, which group may ormay not have a substituent.

As the five-membered or six-membered heterocyclic group, preference isgiven to pyrrolyl group, imidazolyl group, pyrazolyl grouop, triazolylgroup, pyridyl group and pyridonyl group; in particular, imidazolylgroup is preferable.

As the substituent on the heterocyclic ring, preference is given to analkyl group of C₁ to C₆, a halogen atom, phenyl group and an alkylthiogroup; in particular, a halogen atom is preferable.

Specific examples of the compounds of the present invention are shownhereinbelow in Table 1.

                                      TABLE 1                                     __________________________________________________________________________    Com-                                                                          pound                                                                         No. R.sup.1                                                                           R.sup.2                                                                              R.sup.3                                                                            R.sup.4                                                                            X.sup.1         X.sup.2  X.sup.3                     __________________________________________________________________________     1  H   H      H    methyl                                                                             H               H        H                            2  H   H      H    methyl                                                                             2-(1-imidazolyl)                                                                              H        H                            3  H   H      H    methyl                                                                             3-(1-imidazolyl)                                                                              H        H                            4  H   H      H    methyl                                                                             4-(1-imidazolyl)                                                                              H        H                            5  H   H      H    methyl                                                                             4-fluoro        H        H                            6  H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              H        H                            7  H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-methyl-1-imidazolyl)                                                                     H        H                            8  H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-ethyl-1-imidazolyl)                                                                      H        H                            9  H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-isopropyl-1-imidazolyl)                                                                  H        H                            10 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-propyl-1-imidazolyl)                                                                     H        H                            11 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4(2-phenyl-1-imidazolyl)                                                                      H        H                             12                                                                              H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-iodo-1-imidazolyl)                                                                       H        H                            13 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-methoxy-1-imidazolyl)                                                                    H        H                            14 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-methylthio-1-imidazolyl)                                                                 H        H                            15 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-cyano-1-imidazolyl)                                                                      H        H                            16 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-chloro-1-imidazolyl)                                                                     H        H                            17 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(4-methyl-1-imidazolyl)                                                                     H        H                            18 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(4-methyl-1-imidazolyl)                                                                     H        H                            19 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(5-methyl-1-imidazolyl)                                                                     H        H                            20 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-fluoromethyl-1-imidazolyl)                                                               H        H                            21 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-difluoromethyl-1-imidazolyl)                                                             H        H                            22 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-trifluoromethyl-1-imidazolyl)                                                            H        H                            23 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(4,5-dichloro-1-imidazolyl)                                                                 H        H                            24 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-fluoro H                            25 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-chloro H                            26 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-bromo  H                            27 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-iodo   H                            28 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-cyano  H                            29 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-methyl H                            30 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-ethyl  H                            31 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-isopropyl                                                                            H                            32 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-propyl H                            33 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-methoxy                                                                              H                            34 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-ethoxy H                            35 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-isopropoxy                                                                           H                            36 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-propoxy                                                                              H                             37                                                                              H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-trifluoromethyl                                                                      H                            38 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              H        H                            39 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-methyl-1-imidazolyl)                                                                     H        H                            40 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-ethyl-1-imidazolyl)                                                                      H        H                            41 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-isopropyl-1-imidazolyl)                                                                  H        H                            42 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-propyl-1-imidazolyl)                                                                     H        H                            43 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-phenyl-1-imidazolyl)                                                                     H        H                            44 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-iodo-1-imidazolyl)                                                                       H        H                            45 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-methoxy-1-imidazolyl)                                                                    H        H                            46 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-methylthio-1-imidazolyl)                                                                 H        H                            47 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-cyano-1-imidazolyl)                                                                      H        H                            48 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-chloro-1-imidazolyl)                                                                     H        H                            49 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-methyl-1-imidazolyl)                                                                     H        H                            50 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(4-methyl-1-imidazolyl)                                                                     H        H                            51 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(5-methyl-1-imidazolyl)                                                                     H        H                            52 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-fluoromethyl-1-imidazolyl)                                                               H        H                            53 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-difluoromethyl-1-imidazolyl)                                                             H        H                            54 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-trifluoromethyl-1-imidazolyl)                                                            H        H                            55 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(4,5-dichloro-1-imidazolyl)                                                                 H        H                            56 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-fluoro H                            57 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-chloro H                            58 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-bromo  H                            59 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-iodo   H                            60 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-cyano  H                            61 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-methyl H                             62                                                                              H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-ethyl  H                            63 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-isopropyl                                                                            H                            64 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-propyl H                            65 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-methoxy                                                                              H                            66 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-ethoxy H                            67 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-isopropoxy                                                                           H                            68 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-propoxy                                                                              H                            69 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-trifluoromethyl                                                                      H                            70 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              H        H                            71 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-methoxy-1-imidazolyl)                                                                    H        H                            72 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-methylthio-1-imidazolyl)                                                                 H        H                            73 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              H        H                            74 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-methyl-1-imidazolyl)                                                                     H        H                            75 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-ethyl-1-imidazolyl)                                                                      H        H                            76 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-isopropyl-1-imidazolyl)                                                                  H        H                            77 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-propyl-1-imidazolyl)                                                                     H        H                            78 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-phenyl-1-imidazolyl)                                                                     H        H                            79 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-iodo-1-imidazolyl)                                                                       H        H                            80 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-methoxy-1-imidazolyl)                                                                    H        H                            81 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-methylthio-1-imidazolyl)                                                                 H        H                            82 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-cyano-1-imidazolyl)                                                                      H        H                            83 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-chloro-1-imidazolyl)                                                                     H        H                            84 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-metyl-1-imidazolyl)                                                                      H        H                            85 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(4-metyl-1-imidazolyl)                                                                      H        H                            86 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(5-metyl-1-imidazolyl)                                                                      H        H                             87                                                                              H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-fluoromethyl-1-imidazolyl)                                                               H        H                            88 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-difluoromethyl-1-imidazolyl)                                                             H        H                            89 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-trifluoromethyl-1-imidazolyl)                                                            H        H                            90 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(4,5-dichloro-1-imidazolyl)                                                                 H        H                            91 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-fluoro H                            92 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-chloro H                            93 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-bromo  H                            94 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-iodo   H                            95 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-cyano  H                            96 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-methyl H                            97 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-ethyl  H                            98 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-isopropyl                                                                            H                            99 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-propyl H                           100 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-methoxy                                                                              H                           101 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-ethoxy H                           102 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-isopropoxy                                                                           H                           103 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-propoxy                                                                              H                           104 H   H      --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-trifluoromethyl                                                                      H                           105 H   H      methyl                                                                             methyl                                                                             H               H        H                           106 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              H        H                           107 H   H      methyl                                                                             methyl                                                                             4-(2-methyl-1-imidazolyl)                                                                     H        H                           108 H   H      methyl                                                                             methyl                                                                             4-(2-ethyl-1-imidazolyl)                                                                      H        H                           109 H   H      methyl                                                                             methyl                                                                             4-(2-isopropyl-1-imidazolyl)                                                                  H        H                           110 H   H      methyl                                                                             methyl                                                                             4-(2-propyl-1-imidazolyl)                                                                     H        H                           111 H   H      methyl                                                                             methyl                                                                             4-(2-phenyl-1-imidazolyl)                                                                     H        H                           112 H   H      methyl                                                                             methyl                                                                             4-(2-iodo-1-imidazolyl)                                                                       H        H                           113 H   H      methyl                                                                             methyl                                                                             4-(2-methoxy-1-imidazolyl)                                                                    H        H                           114 H   H      methyl                                                                             methyl                                                                             4-(2-methylthio-1-imidazolyl)                                                                 H        H                           115 H   H      methyl                                                                             methyl                                                                             4-(2-cyano-1-imidazolyl)                                                                      H        H                           116 H   H      methyl                                                                             methyl                                                                             4-(2-chloro-1-imidazolyl)                                                                     H        H                           117 H   H      methyl                                                                             methyl                                                                             4-(2-methyl-1-imidazolyl)                                                                     H        H                           118 H   H      methyl                                                                             methyl                                                                             4-(4-methyl-1-imidazolyl)                                                                     H        H                           119 H   H      methyl                                                                             methyl                                                                             4-(5-methyl-1-imidazolyl)                                                                     H        H                           120 H   H      methyl                                                                             methyl                                                                             4-(2-fluoromethyl-1-imidazolyl)                                                               H        H                           121 H   H      methyl                                                                             methyl                                                                             4-(2-difluoromethyl-1-imidazolyl)                                                             H        H                           122 H   H      methyl                                                                             methyl                                                                             4-(2-trifluoromethyl-1-imidazolyl)                                                            H        H                           123 H   H      methyl                                                                             methyl                                                                             4-(4,5-dichloro-1-imidazolyl)                                                                 H        H                           124 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-fluoro H                           125 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-chloro H                           126 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-bromo  H                           127 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-iodo   H                           128 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-cyano  H                           129 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-methy  H                           130 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-ethyl  H                           131 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-isopropyl                                                                            H                           132 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-propyl H                           133 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-methoxy                                                                              H                           134 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-ethoxy H                           135 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-isopropoxy                                                                           H                           136 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-propoxy                                                                              H                           137 H   H      methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-trifluoromethyl                                                                      H                           138 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              H        H                           139 H   H      methyl                                                                             methyl                                                                             3-(2-methyl-1-imidazolyl)                                                                     H        H                           140 H   H      methyl                                                                             methyl                                                                             3-(2-ethyl-1-imidazolyl)                                                                      H        H                           141 H   H      methyl                                                                             methyl                                                                             3-(2-isopropyl-1-imidazolyl)                                                                  H        H                           142 H   H      methyl                                                                             methyl                                                                             3-(2-propyl-1-imidazolyl)                                                                     H        H                           143 H   H      methyl                                                                             methyl                                                                             3-(2-phenyl-1-imidazolyl)                                                                     H        H                           144 H   H      methyl                                                                             methyl                                                                             3-(2-iodo-1-imidazolyl)                                                                       H        H                           145 H   H      methyl                                                                             methyl                                                                             3-(2-methoxy-1-imidazolyl)                                                                    H        H                           146 H   H      methyl                                                                             methyl                                                                             3-(2-methylthio-1-imidazolyl)                                                                 H        H                           147 H   H      methyl                                                                             methyl                                                                             3-(2-cyano-1-imidazolyl)                                                                      H        H                           148 H   H      methyl                                                                             methyl                                                                             3-(2-chloro-1-imidazolyl)                                                                     H        H                           149 H   H      methyl                                                                             methyl                                                                             3-(2-methyl-1-imidazolyl)                                                                     H        H                           150 H   H      methyl                                                                             methyl                                                                             3-(4-methyl-1-imidazolyl)                                                                     H        H                           151 H   H      methyl                                                                             methyl                                                                             3-(5-methyl-1-imidazolyl)                                                                     H        H                           152 H   H      methyl                                                                             methyl                                                                             3-(2-fluoromethyl-1-imidazolyl)                                                               H        H                           153 H   H      methyl                                                                             methyl                                                                             3-(2-difluoromethyl-1-imidazolyl)                                                             H        H                           154 H   H      methyl                                                                             methyl                                                                             3-(2-trifluoromethyl-1-imidazolyl)                                                            H        H                           155 H   H      methyl                                                                             methyl                                                                             3-(4,5-dichloro-1-imidazolyl)                                                                 H        H                           156 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-fluoro H                           157 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-chloro H                           158 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-bromo  H                           159 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-iodo   H                           160 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-cyano  H                           161 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-methyl H                           162 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-ethyl  H                           163 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-isopropyl                                                                            H                           164 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-propyl H                           165 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-methoxy                                                                              H                           166 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-ethoxy H                           167 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-isopropoxy                                                                           H                           168 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-propoxy                                                                              H                           169 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-trifluoromethyl                                                                      H                           170 H   H      methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              H        H                           171 H   H      methyl                                                                             methyl                                                                             3-(2-methoxy-1-imidazoly)                                                                     H        H                           172 H   H      methyl                                                                             methyl                                                                             3-(2-methythio-1-imidazolyl)                                                                  H        H                           173 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              H        H                           174 H   H      methyl                                                                             methyl                                                                             2-(2-methyl-1-imidazolyl)                                                                     H        H                           175 H   H      methyl                                                                             methyl                                                                             2-(2-ethyl-1-imidazolyl)                                                                      H        H                           176 H   H      methyl                                                                             methyl                                                                             2-(2-isopropyl-1-imidazolyl)                                                                  H        H                           177 H   H      methyl                                                                             methyl                                                                             2-(2-propyl-1-imidazolyl)                                                                     H        H                           178 H   H      methyl                                                                             methyl                                                                             2-(2-phenyl-1-imidazolyl)                                                                     H        H                           179 H   H      methyl                                                                             methyl                                                                             2-(2-iodo-1-imidazolyl)                                                                       H        H                           180 H   H      methyl                                                                             methyl                                                                             2-(2-methoxy-1-imidazolyl)                                                                    H        H                           181 H   H      methyl                                                                             methyl                                                                             2-(2-methylthio-1-imidazolyl)                                                                 H        H                           182 H   H      methyl                                                                             methyl                                                                             2-(2-cyano-1-imidazolyl)                                                                      H        H                           183 H   H      methyl                                                                             methyl                                                                             2-(2-chloro-1-imidazolyl)                                                                     H        H                           184 H   H      methyl                                                                             methyl                                                                             2-(2-methyl-1-imidazolyl)                                                                     H        H                           185 H   H      methyl                                                                             methyl                                                                             2-(4-methyl-1-imidazolyl)                                                                     H        H                           186 H   H      methyl                                                                             methyl                                                                             2-(5-methyl-1-imidazolyl)                                                                     H        H                           187 H   H      methyl                                                                             methyl                                                                             2-(2-fluoromethyl-1-imidazolyl)                                                               H        H                           188 H   H      methyl                                                                             methyl                                                                             2-(2-difluoromethyl-1-imidazolyl)                                                             H        H                           189 H   H      methyl                                                                             methyl                                                                             2-(2-trifluoromethyl-1-imidazolyl)                                                            H        H                           190 H   H      methyl                                                                             methyl                                                                             2-(4,5-dichloro-1-imidazolyl)                                                                 H        H                           191 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-fluoro H                           192 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-chloro H                           193 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-bromo  H                           194 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-iodo   H                           195 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-cyano  H                           196 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-methyl H                           197 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-ethyl  H                           198 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-isopropyl                                                                            H                           199 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-propyl H                           200 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-methoxy                                                                              H                           201 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-ethoxy H                           202 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-isopropoxy                                                                           H                           203 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-propoxy                                                                              H                           204 H   H      methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-trifluoromethyl                                                                      H                           205 H   H      methyl                                                                             methyl                                                                             4-cyano         H        H                           206 H   H      methyl                                                                             methyl                                                                             4-chloro        H        H                           207 H   methyl H    H    H               H        H                           208 H   methyl H    H    4-fluoro        H        H                           209 H   methyl H    H    4-methoxy       H        H                           210 H   methyl H    H    2-(1-imidazolyl)                                                                              H        H                           211 H   methyl H    H    3-(1-imidazolyl)                                                                              H        H                           212 H   methyl H    H    4-(1-imidazolyl)                                                                              H        H                           213 H   methyl H    H    4-(1-imidazolyl)                                                                              3-chloro H                           214 H   methyl H    ethyl                                                                              4-(1-imidazolyl)                                                                              H        H                           215 H   methyl H    isopropyl                                                                          4-(1-imidazolyl)                                                                              H        H                           216 H   methyl H    propyl                                                                             4-(1-imidazolyl)                                                                              H        H                           217 H   methyl H    hexyl                                                                              H               H        H                           218 H   methyl methyl                                                                             methyl                                                                             4-methyl        H        H                           219 H   methyl methyl                                                                             methyl                                                                             4-methoxy       H        H                           220 H   methyl methyl                                                                             methyl                                                                             4-dimethylamino H        H                           221 H   methyl methyl                                                                             methyl                                                                             4-fluoro        H        H                           222 H   methyl methyl                                                                             methyl                                                                             4-bromo         H        H                           223 H   methyl methyl                                                                             methyl                                                                             4-chloro        H        H                           224 H   methyl methyl                                                                             methyl                                                                             4-cyano         H        H                           225 H   methyl methyl                                                                             methyl                                                                             4-trifluoromethy                                                                              H        H                           226 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              H        H                           227 H   methyl methyl                                                                             methyl                                                                             4-(2-methyl-1-imidazolyl)                                                                     H        H                           228 H   methyl methyl                                                                             methyl                                                                             4-(2-ethyl-1-imidazolyl)                                                                      H        H                           229 H   methyl methyl                                                                             methyl                                                                             4-(2-isopropyl-1-imidazolyl)                                                                  H        H                           230 H   methyl methyl                                                                             methyl                                                                             4-(2-propyl-1-imidazolyl)                                                                     H        H                           231 H   methyl methyl                                                                             methyl                                                                             4-(2-phenyl-1-imidazolyl)                                                                     H        H                           232 H   methyl methyl                                                                             methyl                                                                             4-(2-iodo-1-imidazolyl)                                                                       H        H                           233 H   methyl methyl                                                                             methyl                                                                             4-(2-methoxyl-1-imidazolyl)                                                                   H        H                           234 H   methyl methyl                                                                             methyl                                                                             4-(2-methylthio-1-imidazolyl)                                                                 H        H                           235 H   methyl methyl                                                                             methyl                                                                             4-(2-cyano-1-imidazolyl)                                                                      H        H                           236 H   methyl methyl                                                                             methyl                                                                             4-(2-chloro-1-imidazolyl)                                                                     H        H                           237 H   methyl methyl                                                                             methyl                                                                             4-(2-methyl-1-imidazolyl)                                                                     H        H                           238 H   methyl methyl                                                                             methyl                                                                             4-(4-methyl-1-imidazolyl)                                                                     H        H                           239 H   methyl methyl                                                                             methyl                                                                             4-(5-methyl-1-imidazolyl)                                                                     H        H                           240 H   methyl methyl                                                                             methyl                                                                             4-(2-fluoromethyl-1-imidazolyl)                                                               H        H                           241 H   methyl methyl                                                                             methyl                                                                             4-(2-difluoromethyl-1-imidazolyl)                                                             H        H                           242 H   methyl methyl                                                                             methyl                                                                             4-(2-trimethyl-1-imidazolyl)                                                                  H        H                           243 H   methyl methyl                                                                             methyl                                                                             4-(4,5-dichloro-1-imidazolyl)                                                                 H        H                           244 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-fluoro H                           245 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-chloro H                           246 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-bromo  H                           247 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-iodo   H                           248 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-cyano  H                           249 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-methyl H                           250 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-ethyl  H                           251 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-isopropyl                                                                            H                           252 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-propyl H                           253 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-methoxy                                                                              H                           254 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-ethoxy H                           255 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-isopropoxy                                                                           H                           256 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-propoxy                                                                              H                           257 H   methyl methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              3-trifluoromethyl                                                                      H                           258 H   methyl methyl                                                                             methyl                                                                             4-(2-pyridyl)   H        H                           259 H   methyl methyl                                                                             methyl                                                                             4-(4-pyridyl)   H        H                           260 H   methyl methyl                                                                             methyl                                                                             4-(3-pyridyl)   H        H                           261 H   methyl methyl                                                                             methyl                                                                             3-fluoro        H        H                           262 H   methyl methyl                                                                             methyl                                                                             3-chloro        H        H                           263 H   methyl methyl                                                                             methyl                                                                             3-methyl        H        H                           264 H   methyl methyl                                                                             methyl                                                                             3-methoxy       H        H                           265 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              H        H                           266 H   methyl methyl                                                                             methyl                                                                             3-(2-ethyl-1-imidazolyl)                                                                      H        H                           267 H   methyl methyl                                                                             methyl                                                                             3-(2-isopropyl-1-imidazolyl)                                                                  H        H                           268 H   methyl methyl                                                                             methyl                                                                             3-(2-propyl-1-imidazolyl)                                H                                                                         269 H   methyl methyl                                                                             methyl                                                                             3-(2-phenyl-1-imidazolyl)                                                                     H        H                           270 H   methyl methyl                                                                             methyl                                                                             3-(2-iodo-1-imidazolyl)                                                                       H        H                           271 H   methyl methyl                                                                             methyl                                                                             3-(2-methoxyy-1-imidazolyl)                                                                   H        H                           272 H   methyl methyl                                                                             methyl                                                                             3-(2-methylthio-1-imidazolyl)                                                                 H        H                           273 H   methyl methyl                                                                             methyl                                                                             3-(2-cyano-1-imidazolyl)                                                                      H        H                           274 H   methyl methyl                                                                             methyl                                                                             3-(2-chloro-1-imidazolyl)                                                                     H        H                           275 H   methyl methyl                                                                             methyl                                                                             3-(2-methyl-1-imidazolyl)                                                                     H        H                           276 H   methyl methyl                                                                             methyl                                                                             3-(4-methyl-1-imidazolyl)                                                                     H        H                           277 H   methyl methyl                                                                             methyl                                                                             3-(5-methyl-1-imidazolyl)                                                                     H        H                           278 H   methyl methyl                                                                             methyl                                                                             3-(2-fluoromethyl-1-imidazolyl)                                                               H        H                           279 H   methyl methyl                                                                             methyl                                                                             3-(2-difluoromethyl-1-imidazolyl)                                                             H        H                           280 H   methyl methyl                                                                             methyl                                                                             3-(2-trifluoromethyl-1-imidazolyl)                                                            H        H                           281 H   methyl methyl                                                                             methyl                                                                             3-(4,5-dichloro-1-imidazolyl)                                                                 H        H                           282 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-fluoro H                           283 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-chloro H                           284 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-bromo  H                           285 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-iodo   H                           286 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-cyano  H                           287 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-methyl H                           288 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-ethyl  H                           289 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-isopropyl                                                                            H                           290 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-propyl H                           291 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-methoxy                                                                              H                           292 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-ethoxy H                           293 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-isopropoxy                                                                           H                           294 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-propoxy                                                                              H                           295 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              4-trifluoromethyl                                                                      H                           296 H   methyl methyl                                                                             methyl                                                                             3-(1-imidazolyl)                                                                              H        H                           297 H   methyl methyl                                                                             methyl                                                                             3-(2-methoxy-1-imidazolyl)                                                                    H        H                           298 H   methyl methyl                                                                             methyl                                                                             3-(2-methylthio-1-imidazolyl)                                                                 H        H                           299 H   methyl methyl                                                                             methyl                                                                             3-(2-pyridyl)   H        H                           300 H   methyl methyl                                                                             methyl                                                                             3-(3-pyridyl)   H        H                           301 H   methyl methyl                                                                             methyl                                                                             3-(4-pyridyl)   H        H                           302 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              H        H                           303 H   methyl methyl                                                                             methyl                                                                             2-(2-methyl-1-imidazolyl)                                                                     H        H                           304 H   methyl methyl                                                                             methyl                                                                             2-(2-ethyl-1-imidazolyl)                                                                      H        H                           305 H   methyl methyl                                                                             methyl                                                                             2-(2-isopropyl-1-imidazolyl)                                                                  H        H                           306 H   methyl methyl                                                                             methyl                                                                             2-(2-propyl-1-imidazolyl)                                                                     H        H                           307 H   methyl methyl                                                                             methyl                                                                             2-(2-phenyl-1-imidazolyl)                                                                     H        H                           308 H   methyl methyl                                                                             methyl                                                                             2-(2-iodo-1-imidazolyl)                                                                       H        H                           309 H   methyl methyl                                                                             methyl                                                                             2-(2-methoxy-1-imidazolyl)                                                                    H        H                           310 H   methyl methyl                                                                             methyl                                                                             2-(2-methylthio-1-imidazolyl)                                                                 H        H                           311 H   methyl methyl                                                                             methyl                                                                             2-(2-cyano-1-imidazolyl)                                                                      H        H                           312 H   methyl methyl                                                                             methyl                                                                             2-(2-chloro-1-imidazolyl)                                                                     H        H                           313 H   methyl methyl                                                                             methyl                                                                             2-(2-methyl-1-imidazolyl)                                                                     H        H                           314 H   methyl methyl                                                                             methyl                                                                             2-(4-methyl-1-imidazolyl)                                                                     H        H                           315 H   methyl methyl                                                                             methyl                                                                             2-(5-methyl-1-imidazolyl)                                                                     H        H                           316 H   methyl methyl                                                                             methyl                                                                             2-(2-fluoromethyl-1-imidazolyl)                                                               H        H                           317 H   methyl methyl                                                                             methyl                                                                             2-(2-difluoromethyl-1-imidazolyl)                                                             H        H                           318 H   methyl methyl                                                                             methyl                                                                             2-(2-trifluoromethyl-1-imidazolyl)                                                            H        H                           319 H   methyl methyl                                                                             methyl                                                                             2-(4,5-dichloro-1-imidazolyl)                                                                 H        H                           320 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-fluoro H                           321 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-chloro H                           322 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-bromo  H                           323 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-iodo   H                           324 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-cyano  H                           325 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-methyl H                           326 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-ethyl  H                           327 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-isopropyl                                                                            H                           328 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-propyl H                           329 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-methoxy                                                                              H                           330 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-ethoxy H                           331 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-isopropoxy                                                                           H                           332 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-propoxy                                                                              H                           333 H   methyl methyl                                                                             methyl                                                                             2-(1-imidazolyl)                                                                              3-trifluoromethyl                                                                      H                           334 H   methyl methyl                                                                             methyl                                                                             3-(2-pyridyl)   H        H                           335 H   methyl methyl                                                                             methyl                                                                             3-(3-pyridyl)   H        H                           336 H   methyl methyl                                                                             methyl                                                                             3-(4-pyridyl)   H        H                           337 H   methyl methyl                                                                             methyl                                                                             3-methoxy       4-methoxy                                                                              5-methoxy                   338 H   methyl ethyl                                                                              ethyl                                                                              4-(1-imidazolyl)                                                                              H        H                           339 H   methyl ethyl                                                                              ethyl                                                                              4-(1-imidazolyl)                                                                              3-fluoro H                           340 H   methyl hexyl                                                                              hexyl                                                                              4-(1-imidazolyl)                                                                              H        H                           341 H   methyl methyl                                                                             hexyl                                                                              4-(1-imidazolyl)                                                                              H        H                           342 H   methyl --CH.sub.2 CH.sub.2 --                                                                  4-(1-imidazolyl)                                                                              H        H                           343 H   methyl --CH.sub.2 CH.sub.2 --                                                                  3-(1-imidazolyl)                                                                              H        H                           344 H   methyl --CH.sub.2 CH.sub.2 --                                                                  2-(1-imidazolyl)                                                                              H        H                           345 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         H               H        H                           346 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-fluoro        H        H                           347 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-chloro        H        H                           348 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-bromo         H        H                           349 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-iodo          H        H                           350 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-methyl        H        H                           351 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-methoxy       H        H                           352 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-trifluoromethyl                                                                             H        H                           353 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-cyano         H        H                           354 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-nitro         H        H                           355 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-dimethylamino H        H                           356 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              H        H                           357 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-methyl-1-imidazolyl)                                                                     H        H                           358 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-ethyl-1-imidazolyl)                                                                      H        H                           359 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-isopropyl-1-imidazolyl)                                                                  H        H                           360 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-propyl-1-imidazolyl)                                                                     H        H                           361 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-phenyl-1-imidazolyl)                                                                     H        H                           362 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-iodo-1-imidazolyl)                                                                       H        H                           363 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-methoxy-1-imidazolyl)                                                                    H        H                           364 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-methylthio-1-imidazolyl)                                                                 H        H                           365 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-cyano-1-imidazolyl)                                                                      H        H                           366 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-chloro-1-imidazolyl)                                                                     H        H                           367 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-methyl-1-imidazolyl)                                                                     H        H                           368 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(4-methyl-1-imidazolyl)                                                                     H        H                           369 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(5-methyl-1-imidazolyl)                                                                     H        H                           370 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-fluoromethyl-1-imidazolyl)                                                               H        H                           371 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-difluoromethyl-1-imidazolyl)                                                             H        H                           372 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-trifluoro-1-imidazolyl)                                                                  H        H                           373 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(4,5-dichloro-1-imidazolyl)                                                                 H        H                           374 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-fluoro H                           375 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-chloro H                           376 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-bromo  H                           377 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-iodo   H                           378 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-cyano  H                           379 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-methyl H                           380 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-ethyl  H                           381 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-isopropyl                                                                            H                           382 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-propyl H                           383 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-methoxy                                                                              H                           384 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-ethoxy H                           385 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-isopropoxy                                                                           H                           386 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-propoxy                                                                              H                           387 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              3-trifluoromethyl                                                                      H                           388 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-pyridyl)   H        H                           389 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(3-pyridyl)   H        H                           390 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(4-pyridyl)   H        H                           391 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-fluoro        H        H                           392 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-chloro        H        H                           393 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-cyano         H        H                           394 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-methyl        H        H                           395 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-methoxy       H        H                           396 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              H        H                           397 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-methyl-1-imidazolyl)                                                                     H        H                           398 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-ethyl-1-imidazolyl)                                                                      H        H                           399 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-isopropyl-1-imidazolyl)                                                                  H        H                           400 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-propyl-1-imidazolyl)                                                                     H        H                           401 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-phenyl-1-imidazolyl)                                                                     H        H                           402 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-iodo-1-imidazolyl)                                                                       H        H                           403 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-methoxy-1-imidazolyl)                                                                    H        H                           404 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-methylthio-1-imidazolyl)                                                                 H        H                           405 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-cyano-1-imidazolyl)                                                                      H        H                           406 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-chloro-1-imidazolyl)                                                                     H        H                           407 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-methyl-1-imidazolyl)                                                                     H        H                           408 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(4-methyl-1-imidazolyl)                                                                     H        H                           409 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(5-methyl-1-imidazolyl)                                                                     H        H                           410 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-fluoromethyl-1-imidazolyl)                                                               H        H                           411 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-difluoromethyl-1-imidazolyl)                                                             H        H                           412 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-trifluoromethyl-1-imidazolyl)                                                            H        H                           413 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(4,5dichloro-1-imidazolyl)                                                                  H        H                           414 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-fluoro H                           415 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-chloro H                           416 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-bromo  H                           417 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-iodo   H                           418 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-cyano  H                           419 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-methyl H                           420 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-ethyl  H                           421 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-isopropyl                                                                            H                           422 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-propyl H                           423 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-methoxy                                                                              H                           424 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-ethoxy H                           425 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-isopropoxy                                                                           H                           426 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-propoxy                                                                              H                           427 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-trifluoromethyl                                                                      H                           428 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              H        H                           429 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-methoxy-1-imidazolyl)                                                                    H        H                           430 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-methylthio-1-imidazolyl)                                                                 H        H                           431 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(2-pyridyl)   H        H                           432 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(3-pyridyl)   H        H                           433 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(4-pyridyl)   H        H                           434 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-trifluoromethyl                                                                             4-chloro H                           435 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-methoxy       4-methoxy                                                                              H                           436 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-pyrrolyl)  H        H                           437 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-pyrazolyl) H        H                           438 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-(1,2,4-triazolyl))                                                                       H        H                           439 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-(2-pyridonyl))                                                                           H        H                           440 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-imidazolyl)                                                                              H        H                           441 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-pyridyl)   H        H                           442 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(3-pyridyl)   H        H                           443 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(4-pyridyl)   H        H                           444 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-thiazolyl) H        H                           445 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-thiazolyl) H        H                           446 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-oxazolyl)  H        H                           447 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-oxazolyl)  H        H                           448 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-pyrrolyl)  H        H                           449 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-pyridazinyl)                                                                             H        H                           450 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-pyrimidinyl)                                                                             H        H                           451 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              H        H                           452 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-methyl-1-imidazolyl)                                                                     H        H                           453 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-ethyl-1-imidazolyl)                                                                      H        H                           454 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-isopropyl-1-imidazolyl)                                                                  H        H                           455 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-propyl-1-imidazolyl)                                                                     H        H                           456 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-phenyl-1-imidazolyl)                                                                     H        H                           457 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-iodo-1-imidazolyl)                                                                       H        H                           458 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-methoxy-1-imidazolyl)                                                                    H        H                           459 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-methylthio-1-imidazolyl)                                                                 H        H                           460 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-2-cyano-1-imidazolyl)                                                                       H        H                           461 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-chloro-1-imidazolyl)                                                                     H        H                           462 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-methyl-1-imidazolyl)                                                                     H        H                           463 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(4-methyl-1-imidazolyl)                                                                     H        H                           464 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(5-methyl-1-imidazolyl)                                                                     H        H                           465 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-fluoromethyl-1-imidazolyl)                                                               H        H                           466 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-difluoromethyl-1-imidazolyl)                                                             H        H                           467 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-trifluoromethyl-1-imidazolyl)                                                            H        H                           469 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-fluoro H                           470 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-chloro H                           471 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-bromo  H                           472 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-iodo   H                           473 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-cyano  H                           474 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-methyl H                           475 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-ethyl  H                           476 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-isopropyl                                                                            H                           477 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-propyl H                           478 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-methoxy                                                                              H                           479 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-ethoxy H                           480 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-isopropoxy                                                                           H                           481 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-propoxy                                                                              H                           482 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(1-imidazolyl)                                                                              3-trifluoromethyl                                                                      H                           483 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(2-pyridyl)   H        H                           484 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(3-pyridyl)   H        H                           485 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-(4-pyridyl)   H        H                           486 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-cyano         H        H                           487 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-nitro         4-methoxy                                                                              H                           488 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-chloro        4-chloro H                           489 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-sulfamoyl     H        H                           490 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-propoxy       H        H                           491 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-chloro        4-chloro H                           492 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-cyano         4-cyano  H                           493 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         2-methoxy       4-methoxy                                                                              5-methoxy                   494 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                H               H        H                           495 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                4-fluoro        H        H                           496 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --                                                4-(1-imidazolyl)                                                                              H        H                           497 H   methyl --(CH.sub.2).sub.5 --                                                                   H               H        H                           498 H   ethyl  --(CH.sub.2).sub.5 --                                                                   4-(1-imidazolyl)                                                                              H        H                           499 H   ethyl  --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              H        H                           500 H   ethyl  H    methyl                                                                             4-(1-imidazolyl)                                                                              H        H                           501 H   ethyl  methyl                                                                             methyl                                                                             4-(1-imidazolyl)                                                                              H        H                           502 H   isopropyl                                                                            --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              H        H                           503 H   isoamyl                                                                              --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              H        H                           504 H   cyclopropyl                                                                          --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              H        H                           505 methyl                                                                            methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              H        H                           506 methyl                                                                            ethyl  --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              H        H                           507 --CH.sub.2 CH.sub.2 --                                                                   --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              H        H                           508 --CH.sub.2 CH.sub.2 CH.sub.2 --                                                          --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              H        H                           509 --(CH.sub.2).sub.4 --                                                                    --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         3-(1-imidazolyl)                                                                              4-methoxy                                                                              H                           510 --(CH.sub.2).sub.4 --                                                                    --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              H        H                           511 --(CH.sub.2).sub.5 --                                                                    --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              H        H                           512 H   methyl methyl                                                                             methyl                                                                             3-(2-iodo-1-imidazolyl)                                                                       4-methoxy                                                                              H                           513 H   methyl methyl                                                                             methyl                                                                             3-(2-methyl-1-imidazolyl)                                                                     4-methoxy                                                                              H                           514 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(2-bromo-1-imidazolyl)                                                                      H        H                           515 H   methyl methyl                                                                             methyl                                                                             3-(2-methoxy-1-imidazolyl)                                                                    4-methoxy                                                                              H                           516 H   methyl methyl                                                                             methyl                                                                             3-(2-iodo-1-imidazolyl)                                                                       4-ethoxy H                           517 H   methyl methyl                                                                             methyl                                                                             3-(2-methyl-1-imidazolyl)                                                                     4-ethoxy H                           518 H   methyl --CH.sub.2 CH.sub.2 CH.sub.2 --                                                         4-(1-imidazolyl)                                                                              2-methoxy                                                                              H                           __________________________________________________________________________

The process for producing the compounds of the present invention willnow be explained. The compounds of the present invention can beproduced, for example, by the following route. ##STR4## (wherein R²represents hydrogen atom.) ##STR5## [In the above formula, R¹, R², R³,R⁴, X¹, X² and X³ are the same as defined above; and R⁵ represents analkyl group of C₁ to C₅ or ##STR6## (wherein R⁶ represents an alkylgroup of C₁ to C₅, and Y represents a halogen atom.)]

Synthesis Route A

Synthesis Route A is a process for producing the compound (I) of thepresent invention, by reacting the acetophenone derivative (II) with anisothiocyanate compound. That is, the compounds (I) of the presentinvention can be produced by reacting the acetophenone derivative (II)with an isothiocyanate compounds in the presence of a base, for example,sodium hydride, butyl lithium, lithium diisopropylamide or potassiumt-butoxide, in a solvent at -100° to 100° C. for several minutes toseveral tens hours. Examples of such solvent includes tetrahydrofuran,diethyl ether, N,N-dimethylformamide, and the like, without specificlimitation, if not involved in the reaction.

Synthetic Route B

Synthetic Route B is a process for producing the compounds (I) of thepresent invention, by reacting the dithioester derivative (III) with acorresponding amine compound. That is, the dithioester derivative (III)and the amine compound are reacted together in the presence of a solventnot involved in the reaction, for example, polar solvents such as water,methanol, ethanol, isopropanol, N,N-dimethylformamide, tetrahydrofuran,diethyl ether, etc. or a mixed solvent thereof, or an aromatichydrocarbon such as benzene, toluene, xylene, etc., or in the absence ofa solvent, at -20° to 140° C. for several minutes to 48 hours.

Dithioester derivatives (III) can be synthesized, for example, accordingto the method described hereinbelow. That is, the acetophenonederivative (II) reacts with carbon disulfide in a solvent not involvedin the reaction such as tetrahydrofuran, diethyl ether,N,N-dimethylformamide, etc., in the presence of a base (including, forexample, butyl lithium, lithium diisopropylamide or potassium t-butoxideor the like) at -100° to 50° C. for several minutes to several tenshours, and to the resulting solution is then added a halogenated alkylfor reaction at -50° to 50° C. for several minutes to several tenshours. Otherwise, a 2-halo-1-alkylpyridinium salt is added to theresulting solution along with a base, for example, triethylamine,pyridine, etc., for reaction at -20° to 100° C. for several minutes toseveral tens hours to produce the compound (III).

Other than the routes described above, the compounds of the presentinvention can be produced through a reaction comprising introducing asubstituent (including, for example, nitration reaction) into thebenzene ring of the β-oxo-β-benzenepropanethioamide derivatives.

The compounds of the present invention can be prepared into a variety ofacid addition salts, if the compound has a basic substituent such asnitrogen-containing aromatic heterocyclic group or dialkylamino group,and such salts can be produced by dissolving the compound of the presentinvention in an appropriate solvent such as ethanol, ether, etc.,thereafter adding an acid as it is or after dissolved in a solvent.

The compounds of the present invention have potassium channel openingaction and are useful for treatment of hypertension, asthma,hypersensitive colon syndrome, and enteriris through pharmacologicalactions including blood vessel dilation, bronchial tract dilation,relaxation of gastrointestinal tract smooth muscle, and the like. Thepresent compounds are administered to humans through oral administrationor parenteral administration according to routine methods. Theformulation for oral dose includes granules, microfine granules,powders, tablets, hard capsules, soft capsules, syrups, emulsions,suspensions, or liquid preparations or the like. The formulation forparenteral dose includes injections, suppositories, transcutaneousagents and the like.

The compound represented by the above general formula (I) orpharmaceutically acceptable salts thereof are contained in the aboveformulations, together with routine pharmaceutical additives such assolid or liquid pharmaceutical carriers or excipients, stabilizers,lubricants, sweet flavors, preservatives, suspending agents or the like.

Examples of the solid carriers to be used include galactose, kaolin,sucrose, crystal cellulose, corn starch, talc, agar, pectin, acasia,magnesium stearate, lecithin, sodium chloride, and the like. Examples ofthe liquid carriers include syrup, glycerine, peanut oil,polyvinylpyrrolidone, olive oil, ethanol, benzyl alcohol, propyleneglycol, water and the like.

The dose of the compound of the present invention is 0.01 mg to 1000mg/day, preferably 0.1 mg to 100 mg/day for oral administration, butpreferably, the dose is appropriately modified, depending on the age,sex, pathology, symptom, the presence or absence of concurrent therapy,and the like. The dosage may be administered once/day, or may be dividedinto several times/day with an appropriate interval.

In producing solid formulations, excipients such as lactose, sucrose,carbohydrate, talc, cellulose, dextrin, kaolin, calcium carbonate andthe like are employed. In case of liquid formulations for oraladministration, such as syrups, emulsions, suspensions or liquidpreparations, the above liquid carriers generally employed are usedalong with an appropriate auxiliary such as a lubricant, a suspensionauxiliary, a sweet flavor, a flavor, a coloring agent or a preservative.

EXAMPLES

The present invention will now be explained in details with reference toexamples, but the invention is not limited to the following exampleswithout departing from the gist thereof.

EXAMPLE 1 Synthesis of 4-(1-imidazolyl)-N-methyl-β-oxo-α,α-trimethylenebenzenepropanethioamide

(Compound No. 36 of Table 1) ##STR7##

(In the above formula, Me represents methylene group.)

4-(1-Cyclobutylcarbonylphenyl)-1-imidazole (2.65 g (11.7 mmol)) wasdissolved in 20 ml of tetrahydrofuran, followed by dropwise addition ofa solution of 1.88 g (16.8 mmol) of potassium t-butoxide in 10 ml oftetrahydrofuran at -20° C. and subsequent agitation at the sametemperature for 30 minutes. To the reaction solution was added dropwisea solution of 1.73 g (234 mmol) of methyl isothiocyanate in 5 me oftetrahydrofuran while keeping the temperature at -20° C. or less. Afterthe completion of the dropwise addition, the reaction temperature wasgradually raised for effecting agitation at 0° C. for 2 hours.

To the reaction solution was added water for extraction into chloroform.The organic phase was washed in water and aqueous saturated sodiumchloride solution, dried over sodium sulfate for distilling off thesolvent, and the resulting residue was purified by silica gel columnchromatography (elution solvent; chloroform/methanol=50/1), to yield acrude crystal product. The product was recrystallized in toluene, toproduce 1.45 g of 4-(1-imidazolyl)-N-methyl-β-oxo-α,α-trimethylenebenzenepropanethioamide. (Yield: 41.4%)

Melting point: 185°-187° C.

IR absorption spectrum (KBr tablet): 1670 cm⁻¹ (C═O).

NMR (solvent; CDCl₃, δ value (ppm)): 1.83 (m, 1H), 2.07 (m, 1H), 2.82(m, 2H), 2.98 (m, 2H), 3.12 (d, 3H), 7.23 (s, 1H), 7.25-7.3 (brd, 1H),7.33 (s, 1H), 7.46 (d, 2H), 7.93 (s, 1H), 8.14 (d, 2H).

EXAMPLES 2 to 37

Following the same method as in Example 1, the compounds shown in Table2 were produced.

                                      TABLE 2                                     __________________________________________________________________________         Com-                                                                              Melting   NMR                                                        Example                                                                            pound                                                                             point IR  Solvent; CDCl.sub.3 [(CD.sub.3).sub.2 SO in Example                           3],                                                        No.  No. (°C.)                                                                        (cm.sup.-1)                                                                       δ value (ppm)                                        __________________________________________________________________________     2   208 106-108                                                                             1680                                                                              1.60(d, 3H), 3.17(3H, d), 5.11(q, 1H), 7.14-7.21(m,                           2H),                                                                          8.10-8.16(m, 2H), 8.60(broad, 1H)                           3   212 217-219                                                                             1685                                                                              1.37(d, 3H), 2.94(d, 3H), 4.83(q, 1H), 7.13(s, 1H),                           7.78(d, 2H), 7.85(s, 1H), 7.98(d, 2H), 8.39(s, 1H),                           10.51(1H, broad)DMSO-d6)                                    4   220 189-190                                                                             1643                                                                              1.61(s, 6H), 3.04(s, 6H), 3.12(d, 3H), 6.61(d, 2H),                           7.87(d, 2H)                                                 5   221 120-122                                                                             1660                                                                              1.62(s, 6H), 3.18(d, 3H), 7.02-7.10(m, 2H),                                   7.30(broad, 1H), 7.89-7.96(m, 2H)                           6   222 145   1664                                                                              1.61(s, 6H), 3.17(d, 3H), 7.2-7.3(broad, 1H), 7.54(m,                         2H),                                                                          7.74(m, 2H)                                                 7   226 179   1670                                                                              1.65(s, 6H), 3.20(d, 3H), 7.25(s, 1H), 7.3-7.4(broad,                         1H),                                                                          7.44(d, 2H), 7.96(1s, 1H), 8.06(d, 2H)                      8   261 108.5-110                                                                           1665                                                                              1.62(s, 6H), 3.19(d, 3H), 7.21(m, 1H), 7.2-7.3(broad,                         1H),                                                                          7.37(m, 1H), 7.56(m, 1H), 7.66(m, 1H)                       9   262   101-101.5                                                                         1670                                                                              1.62(s, 6H), 3.19(d, 3H), 7.2-7.4(broad, 1H), 7.32(m,                         1H),                                                                          7.48(m, 1H), 7.75(m, 1H), 7.85(m, 1H)                      10   342 154.5-155.5                                                                         1670                                                                              1.50(m, 2H), 1.86(m, 2H), 3.11(d, 3H), 7.26(s, 1H),                           7.35(s, 1H), 7.49(d, 2H), 7.98(s, 1H), 8.19(d, 2H)         11   345 113-114                                                                             1647                                                                              1.78(m, 1H), 2.05(m, 1H), 2.83(m, 2H), 2.96(m, 2H),                           3.11(d, 3H), 7.41(m, 3H), 7.53(t, 2H), 7.96(d, 2H)         12   346 115-116                                                                             1660                                                                              1.80(m, 1H), 2.02(m, 1H), 2.83(m, 2H), 2.98(m, 2H),                           3.11(d, 3H), 7.09(t, 2H), 7.2-7.4(broad, 1H), 8.02(m,                         2H)                                                        13   347   151.5                                                                             1648                                                                              1.81(m, 1H), 2.202(m, 1H), 2.75-2.85(m, 2H),                                  2.90-3.00(m, 2H), 3.11(d, 3H), 7.2-7.3(drs, 1H),                              7.40(m, 2H), 7.93(m, 2H)                                   14   348 162-163                                                                             1648                                                                              1.81(m, 1H), 2.02(m, 1H), 2.75-2.85(m, 2H),                                   2.90-3.00(m, 2H), 3.11(d, 3H), 7.2-7.3(broad, 1H),                            7.55(m, 2H), 7.85(m, 2H)                                   15   352 11.8.5-119                                                                          1672                                                                              1.82(m, 1H), 2.06(m, 1H), 2.75-2.85(m, 2H),                                   2.93-3.05(m, 2H), 3.12(d, 3H), 7.2-7.3(broad, 1H),                            7.68(m, 2H), 8.10(m, 2H)                                   16   357 230   1670                                                                              1.80(m, 1H), 2.05(m, 1H), 2.41(s, 3H), 2.88(m, 2H),                           3.00(m, 2H), 3.14(d, 3H), 7.02(s, 1H), 7.05(s, 1H),                           7.3-7.4(broad, 1H), 7.37(d, 2H), 8.14(d, 2H)               17   358   135-135.5                                                                         1685                                                                              1.28(t, 3H), 1.80(m, 1H), 2.17(m, 1H), 2.70(q, 2H),                           2.87(m, 2H), 3.00(m, 2H), 3.14(d, 3H), 6.99(s, 1H),                           7.07(s, 1H), 7.35(d, 2H), 7.3-7.4(broad, 1H), 8.13(d,                         2H)                                                        18   359 193-195                                                                             1675                                                                              1.26(d, 6H), 1.76-1.91(m, 1H), 2.01-2.18(m, 1H),                              2.80-3.08(m, 5H), 3.15(d, 3H), 6.94(d, 1H), 7.08(d,                           1H),                                                                          7.34(broad, 1H), 7.35(d, 2H), 8.13(d, 2H)                  19   360 162-164                                                                             1675                                                                              0.90(t, 3H), 1.65-1.90(m, 4H), 2.00-2.15(m, 1H)                               2.64(t, 2H), 2.80-2.92(m, 2H), 2.97-3.08(m, 2H),                              3.15(d, 3H), 6.98(d, 1H), 7.08(d, 1H), 7.35(d, 2H),                           7.42(broad, 1H), 8.12(d, 2H)                               20   361 amorphous                                                                           1670                                                                              1.76-1.90(m, 1H), 2.00-2.16(m, 1H), 2.80-2.89(m, 2H),                         2.93-3.08(m, 2H), 3.13(d, 3H), 7.17(d, 1H),                                   7.24-7.39(m, 9H), 8.01(d, 2H)                              21   362 163-165                                                                             1670                                                                              1.76-1.88(m, 1H), 2.01-2.14(m, 1H), 2.80-2.92(m, 2H),               (decom-   2.97-3.08(m, 2H), 3.15(d, 3H), 7.20(d, 1H), 7.23(d,                           1H),                                                                position) 7.34(broad, 1H), 7.44(d, 2H), 8.14(d, 2H)                  22   368 180   1660                                                                              1.80(m, 1H), 2.05(m, 1H), 2.29(s, 3H), 2.80(m, 2H),                           2.98(m, 2H), 3.12(d, 3H), 7.06(s, 1H), 7.2-7.4(broad,                         1H),                                                                          7.40(d, 2H), 7.65(s, 1H), 8.12(d, 2H)                      23   369   220-220.5                                                                         1685                                                                              1.80(m, 1H), 2.00(m, 1H), 2.22(s, 3H), 2.86(m, 2H),                           3.00(m, 2H), 3.14(d, 3H), 6.93(s, 1H), 7.36(d, 2H),                           7.4-7.5(broad, 1H), 7.58(s, 1H), 8.16(d, 2H)               24   373 184-186                                                                             1665                                                                              1.76-1.92(m, 1H), 2.00-2.18(m, 1H), 2.79-2.91(m, 2H),                         2.96-3.08(m, 2H), 3.14(d, 3H), 7.33(broad, 1H),                               7.45(d, 2H), 7.57(s, 1H), 8.18(d, 2H)                      25   374 162-164                                                                             1670                                                                              1.83(m, 1H), 2.07(m, 1H), 2.87(m, 2H), 2.99(m, 2H),                           3.13(d, 3H), 7.25(s, 1H), 7.32(s, 1H), 7.7-7.9(broad,                         1H),                                                                          7.47(t, 1H), 7.92(s, 1H), 7.95(m, 2H)                      26   375 173   1670                                                                              1.83(m, 1H), 2.05(m, 1H), 2.80-2.90(m, 2H),                                   2.95-3.02(m, 2H), 3.12(d, 3H), 7.19(m, 1H), 7.22(m,                           1H),                                                                          7.2-7.3(broad, 1H), 7.38(d, 1H), 7.75(s, 1H), 8.02(m,                         1H),                                                                          8.23(d, 1H)                                                27   378 156    2250,                                                                            1.85(m, 1H, 2.05(m, 1H), 2.80-2.90(m, 2H),                                1680                                                                              2.95-3.03(m, 2H), 3.12(d, 3H), 7.29(s, 1H), 7.41(m,                           1H),                                                                          7.5-7.6(broad, 1H), 7.50-7.54(d, 1H), 7.94(s, 1H),                            8.38-8.42(m, 1H), 8.50(m, 1H)                              28   392 119.5-120                                                                           1663                                                                              1.81(m, 1H), 2.02(m, 1H), 2.75-2.85(m, 2H),                                   2.92-3.05(m, 2H), 3.11(d, 3H), 7.2-7.3(broad, 1H),                            7.35(t, 1H), 7.50(m, 1H), 7.85(d, 1H), 7.97(d, 1H)         29   396 198   1671                                                                              1.83(m, 1H), 2.05(m, 1H), 2.80-2.90(m, 2H),                                   2.95(m, 2H), 3.13(d, 3H), 7.24(s, 1H), 7.2-7.3(broad,                         1H),                                                                          7.34(s, 1H), 7.50-7.57(m, 2H), 7.80-7.93(m, 2H),                              8.14(s, 1H)                                                30   404 147.5-149.5                                                                         1670                                                                              1.83(m, 1H), 2.07(m, 1H), 2.62(s, 3H), 2.90(m, 2H),                           2.99(m, 2H), 3.13(d, 3H), 7.13(s, 1H), 7.18(s, 1H),                           7.25-7.4(broad, 1H), 7.5-7.6(m, 2H), 8.02-8.06(m, 2H)      31   434 137   1666                                                                              1.82(m, 1H), 2.04(m, 1H), 2.75-2.85(m, 2H),                                   2.93-3.03(m, 2H), 3.11(d, 3H), 7.2-7.3(broad, 1H),                            7.55(m, 1H), 8.12(m, 1H), 8.38(m, 1H)                      32   437 177-179                                                                             1655                                                                              1.80(m, 1H), 2.06(m, 1H). 2.85(m, 2H), 3.01(m, 2H),                           3.12(d, 3H), 6.51(dd, 1H), 7.2-7.4(broad, 1H),                                7.75(d, 1H), 7.77(d, 2H), 7.98(d, 1H), 8.09(d, 2H)         33   438   200-200.5                                                                         1665                                                                              1.80(m, 1H), 2.06(m, 1H), 2.87(m, 2H), 3.00(m, 2H),                           3.12(d, 3H), 7.2-7.3(broad, 1H), 7.79(d, 2H), 8.13(s,                         1H),                                                                          8.16(d, 2H), 8.63(s, 1H)                                   34   439   209-209.5                                                                         1670                                                                              1.80(m, 1H), 2.05(m, 1H), 2.83(m, 1H). 2.98(m, 1H),                           3.12(d, 3H), 6.27(t, 1H), 6.67(d, 1H), 7.29(m, 1H),                           7.2-7.3(broad, 1H), 7.40(m, 1H), 7.46(d, 2H), 8.13(d,                         2H)                                                        35   495 110-111                                                                             1662                                                                              1.58(m, 2H), 1.77(m, 2H), 3.11(d, 3H), 7.05(m, 2H),                           7.1-7.2(broad, 1H), 8.04(m, 2H)                            36   496 175-176                                                                             1673                                                                              1.59(m, 2H), 1.79(m, 2H), 2.4-2.6(m, 4H), 3.13(d,                             3H),                                                                          7.23(s, 1H), 7.33(s, 1H), 7.44(d, 2H), 7.93(s, 1H),                           8.15(d, 2H)                                                37   500 206.5-207.5                                                                         1680                                                                              1.27(t, 3H), 1.61(d, 3H), 3.68(m, 2H), 5.15(q, 1H),                           7.2-7.3(broad, 1H), 7.26(s, 1H), 7.53(d, 2H), 7.99(s,                         1H),                                                                          8.24(d, 2H)                                                38   514 205-207                                                                             1678                                                                              1.76-1.90(m, 1H), 2.01-2.15(m, 1H), 2.80-2.91(m, 2H),                         2.96-3.08(m, 2H), 3.14(d, 3H), 7.16(s, 2H), 7.34(d,                           1H),                                                                          7.46(dd, 2H), 8.14(dd, 2H)                                 39   518 168   1658                                                                              1.75(m, 1H), 2.04(m, 1H), 2.63(m, 2H), 2.90(m, 2H),                           3.17(d, 3H), 3.88(s, 3H), 6.89(d, 1H), 7.04(dd, 1H),                          7.23(d, 1H), 7.31(d, 1H), 7.60(broad, 1H), 7.78(d,         __________________________________________________________________________                       1H)                                                    

REFERENCE EXAMPLE 1 Synthesis of 4-(1-imidazolyl)-S-methyl-β-oxo-α,α-trimethylenebenzenepropane dithioester ##STR8##

4-(1-Cyclobutylcarbonylphenyl)-1-imidazole (1.00 g (4.42 mmol)) wasdissolved in 15 ml of tetrahydrofuran, followed by dropwise addition ofa solution of 0.64 g (5.7 mmol) of potassium t-butoxide in 7 ml oftetrahydrofuran at -30° C. and subsequent agitation at the sametemperature for 20 minutes. To the reaction solution was then addeddropwise a solution of 0.50 g (6.6 mmol) of carbon disulfide in 4 ml oftetrahydrofuran at -20° C. for agitation for 20 minutes, followed bydropwise addition of 0.83 g (5.9 mmol) of methyl iodide in 4 ml oftetrahydrofuran at the same temperature. The reaction temperature wasgradually raised to room temperature for effecting agitation for 30minutes, followed by addition of water for extraction into chloroform.After washing in water and aqueous saturated sodium chloride solutionand drying over sodium sulfate for distilling off the solvent, theresulting crude crystal product was recrystallized in a mixed solvent oftoluene and hexane, to yield 1.06 g of4-(1-imidazolyl)-S-methyl-β-oxo-α,α-trimethylene benzenepropanedithioester. (Yield: 75.4%)

EXAMPLE 40 Synthesis of N-ethyl-4-(1-imidazolyl)-β-oxo-α,α-trimethylenebenzenepropane thioamide

(Compound No. 499 of Table 1) ##STR9##

(In the above formula, Me represents methylene group; and Et representsethyl group.)

4-(1-Imidazolyl) -S-methyloxo-α, α-trimethylene-β-benzenepropanedithioester (315 mg (1.00 mmol)) was dissolved in 10 ml of isopropanol,followed by addition of a solution of 0.18 g (3.9 mmol) of ethylamine in0.8 ml of isopropanol for agitation at room temperature for 2 days.Adding water for extraction into chloroform, the chloroform phase waswashed in water and aqueous saturated sodium chloride solution, driedover sodium sulfate for distilling off the solvent, and the resultingresidue was purified by silica gel column chromatography (elutionsolvent; chloroform), to yield 245 mg ofN-ethyl-4-(1-imidazolyl)-β-oxo-α, α-trimethylenebenzenepropanethioamide.(Yield: 78.6%)

Melting point: 157°-157° C.

IR absorption spectrum (KBr tablet) 167 cm⁻¹ (C═O).

NMR (solvent; CDCl₃, δ value (ppm)): 1.16 (s, 3H), 1.81 (m, 1H), 2.07(m, 1H), 2.87 (m, 2H), 2.98 (m, 2H), 3.62 (m, 2H), 7.05-7.15 (brd, 1H),7.24 (s, 1H), 7.34 (s, 1H), 7.46 (d, 2H), 7.94 (s, 1H), 8.20 (d, 2H).

EXAMPLES 41 to 57

Following the same method as in Example 40, the compounds shown in Table3 were obtained.

                                      TABLE 3                                     __________________________________________________________________________         Com-                                                                              Melting                                                              Example                                                                            pound                                                                             point IR  NMR                                                        No.  No. (°C.)                                                                        (cm.sup.-1)                                                                       Solvent; CDCl.sub.3, δ value (ppm)                   __________________________________________________________________________    41   218  99-101                                                                             1670                                                                              1.61(s, 6H), 2.38(s, 3H), 3.16(d, 3H), 7.18(d, 2H),                           7.29(broad, 1H), 7.78(d, 2H)                               42   219 133-135                                                                             1650                                                                              1.62(s, 6H), 3.16(d, 3H), 3.84(s, 3H), 6.86(d, 2H),                           7.31(broad, 1H), 7.90(d, 2H)                               43   224 oil   1677                                                                              1.62(s, 6H), 3.21(d, 3H), 7.54(broad, 1H), 7.69(d,                            2H),                                                                          7.95(d, 2H)                                                44   263 101-102                                                                             1670                                                                              1.62(s, 6H), 2.36(s, 3H), 3.17(d, 3H), 7.2-7.4(broad,                         3H),                                                                          7.6-7.7(m, 2H)                                             45   264 73.5-74.5                                                                           1675                                                                              1.63(s, 3H), 3.17(d, 3H), 3.80(s, 3H), 7.06(dd, 1H),                          7.2-7.3(broad, 1H), 7.31(d, 1H), 7.43-7.48(m, 2H)          46   265 138   1680                                                                              1.66(s, 3H), 3.20(d, 3H), 7.21(s, 1H), 7.30(s, 1H),                           7.52(m, 2H), 7.6-7.9(broad, 1H), 7.88(m, 2H),                                 8.00(s, 1H)                                                47   302 152.5-163.5                                                                         1680                                                                              1.39(s, 3H), 3.16(d, 3H), 7.07(s, 1H), 7.08(s, 1H),                           7.32(d, 1H), 7l.42(m, 2H), 7.50(m, 1H), 7.53(s, 1H),                          7.7-7.9(broad, 1H)                                         48   338 183-184                                                                             1665                                                                              0.75(t, 6H), 2.1-2.3(m, 4H), 3.22(d, 3H), 7.23(s,                             1H),                                                                          7.32(s, 1H), 7.42(d, 2H), 7.93(s, 1H), 8.08(d, 2H)         49   351 150-151                                                                             1634                                                                              1.80(m, 1H), 2.05(m, 1H), 2.85(m, 2H), 2.95(m, 2H),                           3.10(d, 3H), 3.85(s, 3H), 6.89(d, 2H), 7.40(broad,                            1H),                                                                          7.95(d, 2H)                                                50   423 174-175                                                                             1663                                                                              1.81(m, 1H), 2.04(m, 1H), 2.86(m, 1H), 2.97(m, 2H),                           3.12(d, 3H), 3.93(s, 3H), 7.06(d, 1H), 7.18(s, 1H),                           7.23(s, 1H), 7.2-7.3(broad, 1H), 7.83(s, 1H), 8.03(s,                         1H),                                                                          8.05(dd, 1H)                                               51   435 165-167                                                                             1632                                                                              1.80(m, 1H), 2.05(m, 1H), 2.86(m, 2H), 2.98(m, 2H),                           3.10(d, 3H), 3.90(s, 3H), 3.93(m, 3H), 6.86(d, 1H),                           7.31(broad, 1H), 7.55(d, 1H), 7.64(q, 1H)                  52   436 123.5-124.5                                                                         1665                                                                              1.82(m, 1H), 2.06(m, 1H), 2.85(m, 2H), 3.05(m, 2H),                           3.26(d, 3H), 6.37(m, 2H), 7.14(m, 2H), 7.2-7.3(broad),                        1H),                                                                          7.47(t, 1H), 7.56(m, 1H), 7.82(m, 1H), 8.10(m, 1H)         53   497 124-126                                                                             1665                                                                              1.16-1.32(m, 3H), 1.52-1.74(m, 3H), 1.94-2.12(m, 2H),                         2.40-3.16(m, 2H), 3.16(d, 3H), 7.35-7.53(m, 4H),                              7.80(d, 2H)                                                54   498 189-191                                                                             1665                                                                              1.18(t, 3H), 1.2-1.3(broad, 4H), 1.5-1.65(broad, 2H),                         1.9-2.1(m, 2H), 2.2-2.6(m, 2H), 3.70(m, 2H), 7.24(s,                          1H),                                                                          7.33(s, 1H), 7.43(d, 2H), 7.93(s, 1H), 8.00(d, 2H)         55   503 137-139                                                                             1675                                                                              0.84(d, 6H), 1.37-1.53(m, 3H), 1.75-1.87(m, 1H),                              2.00-2.13(m, 1H), 2.77-2.89(m, 2H), 2.94-3.05(m, 2H),                         3.57-3.64(m, 2H), 7.12(broad, 1H), 7.24(s, 1H),                               7.33(s, 1H),                                                                  7.47(d, 2H), 7.94(s, 1H), 8.15(d, 2H)                      56   505 amorphous                                                                           1665                                                                              1.88-2.12(m, 2H), 2.60-3.40(m, 4H), 2.99(s, 3H),                              3.36(m, 3H), 7.23(s, 1H), 7.32(s, 1H), 7.43(d, 2H),                           7.93(s, 1H), 8.30(d, 2H)                                   57   509   135-135.5                                                                         1667                                                                              1.75-2.0(m, 5H), 2.0-2.15(m, 1H), 2.6-3.2(broad, 4H),                         3.23-3.3(broad, 2H), 3.80(t, 2H), 3.92(s, 3H),                                7.05(d, 1H), 7.18(s, 1H), 7.29(s, 1H), 7.88(s, 1H),                           7.19(d, 1H), 8.21(dd, 1H)                                  __________________________________________________________________________

REFERENCE EXAMPLE 2 ##STR10##

α-Methylpropiophenone (0.75 g (5.0 mmol)) was dissolved in 15 ml oftetrahydrofuran, followed by addition of a solution of 0.61 g (5.5 mmol)of potassium t-butoxide in 15 ml of tetrahydrofuran under ice coolingfor agitation for 45 minutes. To the solution was added 330 μl of carbondisulfide for agitation, under ice cooling, for 1 hour, followed byaddition of 1.40 g (5.5 mmol) of 2-chloro-1-methylpyridinium iodide and550 mg (5.5 mmol) of triethylamine, for agitation for 15 minutes, toproduce the dithioester derivative (IV). Without further treatment, thereaction solution was subjected to the next reaction.

EXAMPLE 58 Synthesis of α,α-dimethyl-β-oxobenzenepropanethioamide(Compound No. 105 of Table 1 ) ##STR11##

To the reaction solution produced in Reference Example 2 was added 1 mlof an aqueous 28% ammonia solution, for agitation for 4 hours.Subsequently, water was added to the reaction solution for extractioninto ethyl acetate. The ethyl acetate phase was washed in water andaqueous saturated sodium chloride solution, dried over sodium sulfatefor distilling off the solvent, and the resulting crude crystal waspurified by silica gel column chromatography (elution solvent; ethylacetate), to yield 160 mg of α,α-dimethyl-β-oxobenzenepropanethioamide.(Yield: 15.4%)

Melting point: 172°-175° C.

IR absorption spectrum (KBr tablet): 1664 cm⁻¹ (C═O).

NMR (solvent; CDCl₃, δ value (ppm)): 1.64 (s, 6H), 7.41 (t, 2H), 7.53(t, 1H), 7.95 (d, 2H).

EXAMPLE 59

Following the same method as in Example 58, 4-(2-pyridyl)-α,α,N-trimethylbenzenepropanethioamide (Compound No. 258 of Table 1) wasobtained. (Yield: 78.6%)

Melting point: 172°-175° C.

IR absorption spectrum (KBr tablet): 1666 cm⁻¹ (C═O).

NMR (solvent; CDCl₃, δ value (ppm)): 1.64 (s, 6H), 3.17 (d, 3H),7.27-7.3 (broad, 1H), 7.54 (m, 2H), 7.74 (m, 2H).

EXAMPLE 60 Synthesis of 4-methoxy-N-methyl-3-nitro-β-oxo-α,α-trimethylenebenzenepropanethioamide

(Compound No. 487 of Table 1) ##STR12##

4-Methoxy-N-methyloxo-α,α-trimethylene-β-benzenepropanethioamide (560 mg(2.1 mmol)) was added to me of fuming nitric acid while keeping thereaction temperature at -40° C. or less. After the termination of theaddition, agitation was further effected at the same temperature for 30minutes. After the termination of the reaction, the reaction solutionwas poured into ice-cold water for extraction into chloroform. Thechloroform phase was washed in water and aqueous saturated sodiumchloride solution, dried over sodium sulfate for distilling off thesolvent, and the resulting residue was purified by silica gel columnchromatography, to produce 140 mg of4-methoxy-N-methyl-3-nitro-β-oxo-α,α-trimethylene benzenepropanethioamide. (Yield: 21.4%)

Melting point: 145°-146° C.

IR absorption spectrum (KBr tablet): 1665 cm⁻¹ (C═O).

NMR (solvent; CDCl₃, δ value (ppm)): 1.81 (m, 1H), 2.06 (m, 1H), 2.84(m, 2H), 2.97 (m, 2H), 3.12 (d, 3H), 4.01 (s, 3H), 7.09 (d, 2H), 7.2-7.3(brd, 1H), 8.23 (dd, 1H), 8.52 (d, 1H).

EXAMPLES 61 to 71

Following the same method as in Example 58, the compounds shown in Table4 were obtained.

                                      TABLE 4                                     __________________________________________________________________________         Com-                                                                              Melting                                                              Example                                                                            pound                                                                             point IR  NMR                                                        No.  No. (°C.)                                                                        (cm.sup.-1)                                                                       Solvent; CDCl.sub.3, δ value (ppm)                   __________________________________________________________________________    61   270 149-151                                                                             1689                                                                              1.67(s, 6H), 3.22(d, 3H), 7.20(m, 2H), 7.50-7.65(m,                           3H),                                                                          7.84(m, 1H), 8.01(m, 1H)                                   62   275 164-165                                                                             1682                                                                              1.65(s, 6H), 2.38(s, 3H), 3.20(d, 3H), 7.02(dd, 2H),                          7.30-7.55(m, 3H), 7.82(m, 1H), 7.93(m, 1H)                 63   291 162   1672                                                                              1.64(s, 6H), 3.18(d, 3H), 3.92(s, 3H), 7.03(d, 1H),                           7.18(d, 1H), 7.19(s, 1H), 7.35(broad, 1H), 7.79(s,                            1H),                                                                          7.95(s, 1H), 8.00(dd, 1H)                                  64   292 amorphous                                                                           1676                                                                              1.43(t, 3H), 1.66(s, 6H), 3.19(d, 3H), 4.16(q, 2H),                           7.01(d, 1H), 7.10(s, 1H), 7.21(s, 1H), 7.77(s, 1H),                           7.94(d, 1H), 8.01(dd, 1H), 8.66(broad, 1H)                 65   305 145-146                                                                             1693                                                                              1.27(d, 6H), 1.46(s, 6H), 2.78(m, 1H), 3.18(d, 3H),                           6.79(d, 1H), 7.03(d, 1H), 7.28-7.33(m, 1H),                                   7.43-7.58(m, 3H), 7.80(s, 1H)                              66   337 192-193                                                                             1678                                                                              1.63(s, 6H), 3.14(d, 3H), 3.82(s, 6H), 3.90(s, 3H),                           7.10(broad, 1H), 7.25(s, 2H)                               67   512 amorphous                                                                           1676                                                                              1.65(s, 6H), 3.19(d, 3H), 3.66(s, 3H), 7.03(d, 1H),                           7.09(d, 1H), 7.19(d, 1H), 7.36(broad, 1H), 7.82(d,                            1H),                                                                          8.12(dd, 1H)                                               68   513 206   1676                                                                              1.64(s, 6H), 2.19(s, 3H), 3.18(d, 3H), 3.86(s, 3H),                           6.88(s, 1H), 7.01(d, 1H), 7.02(s, 1H), 7.51(broad,                            1H),                                                                          7.81(d, 1H), 8.07(dd, 1H)                                  69   515 173.5-174                                                                           1680                                                                              1.64(s, 6H), 3.16(d, 3H), 3.25(s, 3H), 3.85(s, 3H),                           4.36(s, 2H), 6.99(s, 1H), 7.01(d, 1H), 7.35(broad,                            1H),                                                                          7.90(d, 1H), 8.07(dd, 1H)                                  70   516 165-168                                                                             1684                                                                              1.35(t, 3H), 165(s, 6H), 3.19(d, 3H), 4.12(q, 2H),                  (decom-   7.00(d, 1H), 7.08(d, 1H), 7.18(d, 1H), 7.41(broad,                            1H),                                                                position) 7.81(d, 1H), 8.09(dd, 1H)                                  71   517 178-179                                                                             1676                                                                              1.34(t, 3H), 1.64(s, 6H), 2.21(s, 3H), 3.18(d, 3H),                           4.11(q, 2H), 6.87(s, 1H), 6.99(d, 1H), 7.01(s, 1H),                           7.47(broad, 1H), 7.80(d, 1H), 8.03(dd, 1H)                 72    6  185-187                                                                             1671                                                                              1.84(m, 1H), 2.10(m, 1H), 2.9-3.1(m, 4H),                                     6.85(broad, 1H), 7.24(s, 1H), 7.34(s, 1H),                                    7.34(broad, 1H), 7.47(d, 2H), 7.95(s, 1H), 8.14(d,         __________________________________________________________________________                       2H)                                                    

TEST EXAMPLE 1

The aorta thoracic of a Wistar rat was resected and then suspended in aKlebs-Heneleit solution kept at 37° C., according to the Weir andWeston's method (Br. J. Pharmac., 88, 121, (1986)), to determine thedose (IC30 20 mMK) of a drug suppressing 30% of 20 mMK shrinkage. Ascontrol, the same test was done about the known compound A described inBull. Soc. Chem. Fr., 1975, 829.

                  TABLE 5                                                         ______________________________________                                         ##STR13##                Compound A                                          Compound No.  Rat aorta                                                       in Table 1    IC30 20 mMK (μM)                                             ______________________________________                                        224           5.0                                                             226           13.0                                                            265           0.62                                                            356           2.1                                                             357           0.18                                                            Compound A    13.6                                                            ______________________________________                                    

TEST EXAMPLE 2

At a dose of 3 mg/kg or 10 mg/kg, the compound of the present inventionwas orally administered to spontaneous hypertensive rats (OKAMOTO-AOKIstrain) with an average blood pressure of 150 mmHg or more. According tothe direct method described by Nakano H. and Takayanagi K., JapaneseJournal of Pharmacology, Vol. 25, 25 (1975), blood pressure and cardiacoutput were measured. Using the compound A used in the Test Example 1 ascontrol, the same test was done.

The results 2 hours after the dosing are shown in Table 6.

                  TABLE 6                                                         ______________________________________                                                      Mean blood pressure (mm Hg)                                     Compound No.                                                                             Dose     Value prior to                                                                            Blood pressure                                in Table 1 (mg/kg)  dosing      decrease                                      ______________________________________                                        224        10       177.5       38.8                                          226        10       177.3       35.9                                          265         3       163.1       76.5                                          302        10       176.1       51.9                                          342        10       167.3       31.2                                          356        10       172.0       58.9                                          357        10       158.4       78.4                                          Compound A 10       180.3       14.1                                          ______________________________________                                    

What is claimed is:
 1. A β-oxo-β-benzenepropanethioamide derivative of the formula: ##STR14## wherein R¹ and R² independently represent hydrogen, alkyl or 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms, or R¹ and R² taken together represent alkylene of 3-6 carbon atoms; R³ represents hydrogen, alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms; R⁴ represents alkyl of 1-6 carbon atoms or cycloalkyl of 3-6 carbon atoms; or R³ and R⁴ taken together represent alkylene of 2-5 carbon atoms; X¹, X² and X³ independently represent hydrogen, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, cyano, nitro, dialkylamino of 2-12 carbon atoms, sulfamoyl or a five-membered or six-membered heterocyclic group containing 1-3 nitrogen atoms as the heteroatom, which group is unsubstituted or is substituted by alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, cyano, phenyl, alkylthio of 1-6 carbon atoms or haloalkyl of -6 carbon atoms, except for the case where R¹ represents hydrogen, R² represents n-propyl, R³ represents hydrogen, R⁴ represents methyl and X¹, X² and X³ represent hydrogen; and the case where R¹ represents hydrogen, R², R³ and R⁴ represent methyl, and X¹, X² and X³ represent hydrogen, or a pharmaceutically acceptable acid addition salt thereof.
 2. A compound as claimed in claim 1, wherein at least one of X¹, X² and X³ represents halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, cyano, nitro, dialkylamino of 2-12 carbon atoms, sulfamoyl or a five-membered or six-membered heterocyclic group containing 1-3 nitrogen atoms as the hetero atom, which group is unsubstituted or is substituted by alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, cyano, phenyl, alkylthio of 1-6 carbon atoms or haloalkyl of 1-6 carbon atoms.
 3. A compound as claimed in claim 1, wherein at least one of X¹, X² and X³ represents a five-membered or six-membered heterocyclic group containing 1-3 nitrogen atoms as the hetero atom, which group is unsubstituted or is substituted by alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, cyano, phenyl, alkylthio of 1-6 carbon atoms or haloalkyl of 1-6 carbon atoms.
 4. A compound as claimed in claim 3, wherein the five-membered or six-membered heterocyclic group is selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, oxoazolyl, pyridyl, pyridazinyl, pyridazinonyl, pyrrolidionyl, pyridonyl and pyrimidinyl.
 5. A compound as claimed in claim 4, wherein the five-membered or six-membered heterocyclic group is selected from the group consisting of pyrrolyl, imidazolyl, triazolyl, pyridyl and pyridonyl.
 6. A compound as claimed in claim 5, wherein the five-membered or six-membered heterocyclic group is imidazolyl.
 7. A compound as claimed in claim 3, wherein the substituent is selected from the group consisting of alkyl of 1-6 carbon atoms, halogen, phenyl and alkylthio of 1-6 carbon atoms.
 8. A compound as claimed in claim 7, wherein the substituent is halogen.
 9. A pharmaceutical composition containing a pharmaceutically effective amount of a compound as claimed in claim 1 and a pharmaceutically acceptable carrier.
 10. A pharmaceutical composition for potassium channel opening, containing an effective amount of a compound as claimed in claim 1 and a pharmaceutically acceptable carrier. 